Phosphate selective resin and related methods

ABSTRACT

A crosslinked polymer for binding phosphate anions is provided, the polymer comprises a polyvalent cation attached to the polymer through at least one covalently bound anionic functional group, and wherein the anionic group is selected from a group consisting of sulfonate, carboxylate, phosphonate and mixtures thereof and wherein the cation is selected from a group consisting of aluminum, calcium, magnesium, molybdenum, manganese, titanium, barium, strontium, zirconium, vanadium, scandium, lanthanum, yttrium, cerium, nickel, iron, copper, cobalt, chromium, zinc and mixtures thereof.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a hemocompatible polymeric resinfunctionalized to remove phosphate anions from whole blood withoutappreciably effecting the concentration of the other major anions ofchloride and bicarbonate. The polymeric resin is targeted forextracorporal application in conjunction with hemodialysis. Thefunctioning binding agent for the phosphate is a polyvalent cationattached to the polymer via an anionic group.

2. Description of Related Art

People with functioning kidneys have normal phosphate levels in theirblood of 2.5 to 4.5 mg/dl of blood (measured as phosphorus), so that thephosphate anion concentration calculated as a millimole of HPO₄ ²⁻ anionranges within 0.081 to 0.145 mmole per dl (deciliter). At the pH ofblood ranging from 7.35 to 7.45, the predominant monomeric phosphateanion is the monohydrogenphosphate anion, HPO₄ ²⁻. The phosphate anionlevel is held in this narrow concentration range for a healthyhomeostasis by the normal functioning kidney via a check and balancesystem that involves hormones and reabsorption of water and electrolyte(ions) in the tubules of the kidney.

People with End Stage Renal Function or Disease are not able to keep thephosphate level in the blood within the proper normal range when eatinga normal protein diet. Phosphate enters the body primarily throughingested protein. The phosphate level rises out of control with suchindividuals reaching blood levels as high as four times (4×) the normalblood concentration. This condition, known as hyperphosphatemia, ifuntreated allows calcium to be pulled from the bone mass producingdegenerative bone disease.

For people with End Stage Renal Disease (ESRD), the phosphateconcentration in the blood is regulated by either a low protein diet orby ingesting phosphate binders with the food intake. The phosphateanions from the ingested protein are trapped by the binder orsequestrant and are carried out with the feces with only a very smallamount of absorption into the blood from the intestinal tract. Thephosphate binders initially used were aluminum and calcium compounds,but these were found to have moderately severe to very severe sideeffects. More recently (1997–2004), phosphate binding agents have beendeveloped that are anion exchange polymers (RenaGel® and a polymer boundguanidinium hydrochloride) and less toxic inorganic compounds such aslanthanum carbonate tetrahydrate (Fosrenal™), ferric salts of citrateand acetate, and a lanthanum based porous ceramic material (RenaZorb™).All of these phosphate-binding agents are ingested with food and aredesigned to sequester phosphate anions during the digestive process inthe intestinal tract. The absorption through the intestinal wall intothe blood by the bound or sequestered phosphate is hindered and,consequently, the phosphate is carried out by way of the feces.

This invention defines polymeric sequestrants for phosphate anions thatare not ingested with food at mealtime. They function by bindingphosphate anions directly from the blood as part of the hemodialysissystem during the treatment sessions for people with End Stage RenalDisease (ESRD). These polymers function as selective sequestrants forthe divalent monohydrogenphosphate anion and the anions ofpolyphosphoric acids without disturbing the concentrations of the othermajor anions of chloride and bicarbonate. Since bicarbonate is not boundby these sequestrants, the pH of the blood is unaltered during thetreatment session.

SUMMARY OF THE INVENTION

The present invention provides for a crosslinked polymer for bindingphosphate anions wherein the polymer comprises at least one polyvalentcation wherein the cation functions as the binding site for phosphateanions. In another embodiment, the polymer is selected from a groupconsisting of divinylbenzene, styrene, ethylvinylbenzene, acrylic acid,methacrylic acid, esters of acrylic acid, esters of methacrylic acid,maleic acid and esters thereof, itaconic acid and esters thereof,trimethylolpropane trimethacrylate, trimethylolpropane triacrylate, andmixtures thereof.

In still another embodiment, the cation is attached to the polymerthrough at least one anionic group and the anionic group is selectedfrom a group consisting of sulfonate, carboxylate, phosphonate andmixtures thereof. In yet another embodiment, the cation is selected froma group consisting of aluminum, calcium, magnesium, molybdenum,manganese, titanium, barium, strontium, zirconium, vanadium, scandium,lanthanum, yttrium, cerium, nickel, iron, copper, cobalt, chromium, zincand mixtures thereof.

In still yet another embodiment, the polymer is a hemocompatiblepolymer. For purposes of this invention, the term “hemocompatible” isdefined as a condition whereby a material, when placed in contact withwhole blood and blood components or physiological fluids, results inclinically acceptable physiological changes. In a further embodiment,the polymer is a biocompatible polymer. For purposes of the invention,the term “biocompatible” is defined as being able to coexist with bodyfluids—whole blood, blood plasma, and lymph fluid-without initiating anadverse physiologic change within the fluid or at the surfaceinterfacing with the fluid.

The polymer of the present invention can be porous, non-porous ormicroporous. The term “porous polymer” is defined as a polymer particlehaving an internal pore structure with a porosity resulting from voidsor holes throughout the polymer matrix. The term “non-porous polymer” isdefined as an amorphous, gellular material without pores. The term“microporous polymer” is synonymous with non-porous polymer. In stillanother embodiment, the polymer is an ion exchange resin or polymer. Anion exchange resin or polymer is a resin or polymer carrying ionogenicgroups that are capable of exchanging ions or of sequestering ions. Theion exchange polymers of the present invention are beneficial when usedwith blood for removing and isolating varying ions and ionogenicmolecules.

In still a further embodiment, the polymer binds to phosphate in a humanbodily fluid environment, wherein the human bodily fluid environment isselected from a group consisting of whole blood, lymph fluid, bloodplasma and mixtures thereof.

In yet a further embodiment, the present invention relates to acrosslinked polymer for binding phosphate anions, the polymer comprisinga polyvalent cation attached to the polymer through at least onecovalently bound anionic functional group. In still yet a furtherembodiment, the polymer is selected from a group consisting ofdivinylbenzene, styrene, ethylvinylbenzene, acrylic acid, methacrylicacid, esters of acrylic acid, esters of methacrylic acid, maleic acidand esters thereof, itaconic acid and esters thereof, trimethylolpropanetrimethacrylate, trimethylolpropane triacrylate, and mixtures thereof.In another further embodiment, the anionic functional group is selectedfrom a group consisting of sulfonate, carboxylate, phosphonate andmixtures thereof. In still another further embodiment, the cation isselected from a group consisting of aluminum, calcium, magnesium,molybdenum, manganese, titanium, barium, strontium, zirconium, vanadium,scandium, lanthanum, yttrium, cerium, nickel, iron, copper, cobalt,chromium, zinc and mixtures thereof.

In another embodiment, the present invention provides a polymer forremoving phosphate anions from a human bodily fluid environment, thepolymer is manufactured by a method comprising: forming a crosslinkedpolymer, attaching at least one anionic group to the polymer, andbinding at least one polyvalent cation onto the anionic group attachedto the polymer.

In a further embodiment, the present invention relates to a method ofmanufacturing a polymer for binding phosphate anions, the methodcomprising: forming a crosslinked polymer, attaching at least oneanionic group to the polymer, and binding at least one polyvalent cationonto the anionic group attached to the polymer to form a ligand wherebythe ligand is design to remove phosphate anions.

DETAILED DESCRIPTION OF THE INVENTION

As required, detailed embodiments of the present invention are disclosedherein; however, it is to be understood that the disclosed embodimentsare merely exemplary of the invention that may be embodied in variousforms. Therefore, specific functional details disclosed herein are notto be interpreted as limiting, but merely as a basis for the claims andas a representative basis for teaching one skilled in the art to employthe present invention in various ways.

The specific examples below will enable the invention to be betterunderstood. However, they are given merely by way of guidance and do notimply any limitation.

The polymers are prepared in spherical bead geometry by suspensionpolymerization of the monomers in a formulated aqueous phase. Theaqueous phase is formulated to provide droplet stability by a polymericdispersant, to quench aqueous phase polymerization by a water-solublefree radical inhibitor and, where needed, a buffer to maintain a pHabove nine (9.0) during the conversion of the monomer droplets into asuspension of polymer beads.

The polymers are prepared from both aromatic monomers and aliphaticmonomers with crosslinking provided by divinylbenzene (DVB) andtrimethylolpropane trimethacrylate (TMPTMA). The initiator most used isbenzoyl peroxide, although the azo—and peroxydicarbonate—initiators mayalso be used. The polymers in the attached examples are non-porous gelpolymers, although porous polymers may also be prepared and used as theanchoring substrate for the functionality, provided the maximum porediameter is kept under 100 Å so as to exclude protein sorption duringdirect contact with whole blood.

With benzoyl peroxide as the initiator, the polymerizations are carriedout at 70 to 75° C. for five (5) to eight (8) hours followed by atemperature ramp to 95° C. for an additional two (2) hours to decomposeunreacted benzoyl peroxide.

The active group that sorbs the phosphate anions from the blood is anyone of the polyvalent cations (listed in Table 1 below) attached to thepolymeric matrix via covalenty bound anionic groups. The anionic groupsmost used in this invention are sulfonate and carboxylate. The sulfonategroup is covalently bound to the crosslinked aromatic polymer bysulfonation at 80 to 100° C. for four hours with 96 to 99% sulfuricacid. The aromatic polymers are terpolymers of styrene,ethylvinylbenzene (EVB) and varying levels of divinylbenzene (DVB). Thedivinylbenzene is the crosslinking agent that provides the insolubilityto the sulfonated aromatic bead polymers.

The spherical carboxylate polymers are prepared by suspensionpolymerization of acrylate and methacrylate esters in the presence of 3to 5 wt. % sodium sulfate with crosslinking provided by eitherdivinylbenzene or trimethylolpropane trimethacrylate. The ester group istransformed into the carboxylate anion by caustic hydrolysis with 5 wt.% sodium hydroxide, with the methyl esters being the easiest tohydrolyze.

The polyvalent cations are loaded onto the polymer bound anionic groupsvia an ion exchange procedure. The functionalized bead polymers areloaded into a glass column to give a bead bed aspect ratio (bedheight/bed diameter) of 10 to 12. The bead bed is treated downflow witha 3 to 5 wt. % aqueous solution of the nitrate salt of the polyvalentcation at a flow rate of 2 to 4 bed volumes per hour until the effluentexiting the bottom of the column has the composition of the influententering the top of the column. At this point all the counter ionsinitially associated with the anionic groups bound to the polymericmatrix have been displace by the polyvalent cation.

The polyvalent cations that are effective for binding phosphate anionsselectively from whole blood are identified in the attached tabulationset forth below in Table 1:

TABLE 1 Polyvalent Cations to be anchored to the Polymers CationAvailable Salt Solubility MW Al³⁺ Al(NO₃)₃.9H₂O 67.3 g/100 ml H₂O375.134 Ca²⁺ Ca(NO₃)₂.4H₂O 129 g/100 g H₂O 236.149 Mg²⁺ Mg(NO₃)₂.6H₂OSoluble in 0.8 parts H₂O 256.406 Mn²⁺ Mn(NO₃)₂.4H₂O Very Soluble in H₂O251.010 Ti⁴⁺ TiCl₄ Soluble in cold H₂O 189.678 Ba²⁺ Ba(NO₃)₂ 9.27 g/100g H₂O 261.336 Sr²⁺ Sr(NO₃)₂ 40.7 g/100 g H₂O 211.629 Zr⁴⁺ Zr(NO₃)₄.5H₂OVery Soluble in H₂O 429.320 V³⁺ VCl₃ Decomposes in H₂O 157.300 Sc³⁺Sc(NO₃)₃.5H₂O Very Soluble in H₂O 321.047 La³⁺ La(NO₃)₃.6H₂O 136 g/100 gH₂O 433.012 Y³⁺ YCL₃ 78.8 g/100 g H₂O 195.264 Y³⁺ Y(NO₃)₃.6H₂O 123 g/100g H₂O 383.012 Y³⁺ YCl₃.6H₂O 235 g/100 ml H₂O 303.355 Ce³⁺ Ce(NO₃)₃.6H₂OSoluble in H₂O 434.221 Ni²⁺ Ni(NO₃)₂.6H₂O Soluble in 0.4 parts H₂O290.794 Fe³⁺ Fe(NO₃)₃.9H₂O 137.7 g/100 g H₂O 403.997 Cu²⁺ Cu(NO₃)₂.3H₂O137.8 g/100 g H₂O 241.602 Co³⁺ Co(NO₃)₃ Soluble in H₂O 244.948 Co²⁺Co(NO₃)₂.6H₂O 133.8 g/100 ml H₂O 291.034 Cr³⁺ Cr(NO₃)₃.9H₂O 74% H₂O400.148 Zn²⁺ Zn(NO₃)₂.6H₂O 56.1 g/100 g H₂O 297.491 Cr³⁺ CrCl₃.6H₂OSoluble in H₂O 266.445

The dispersion mixture for a five (5) liter reactor for preparing thearomatic polymers is set forth below in Table 2:

TABLE 2 Dispersion Mixture For Five (5) Liter Reactor For PreparingAromatic Polymers Aq/Org. Vol. Ratio 1.1 Volume of Organic Phase 1900 mlVolume of Aqueous Phase 2090 ml Density of Organic Phase 0.905 g/mlWeight of Organic Phase 1720.0 g Density of Aqueous Phase 1.005 g/mlWeight of Aqueous Phase 2100.0 g Polymerizable Monomers; DVB, EVB, andStyrene 1720.0 g Total Volume of Organic and Aqueous Phases 3990.0 mlTotal Weight of Organic and Aqueous Phases 3820.0 g

The aqueous phase composition for preparing the aromatic, crosslinkedpolymers of the present invention is set forth in Table 3 below:

TABLE 3 Aqueous Phase Composition For Preparing Aromatic, CrosslinkedPolymers Ultrapure Water, wt. % 98.700 Dispersant¹ (Pure), wt. % 0.500Sodium Carbonate², wt. % 0.500 Sodium Nitrite², wt. % 0.300 ¹Dispersantmay be any of those listed in Dispersant Table 5. ²Values are foranhydrous salts.

The aqueous phase charges for preparing aromatic, crosslinked polymersin a five (5) liter reactor is set forth in Table 4 below:

TABLE 4 Aqueous Phase Charges For Preparing Aromatic, CrosslinkedPolymers in a Five (5) Liter Reactor Ultrapure Water, g 2072.7Dispersant¹ (Pure), g 10.5 Sodium Carbonate², g 10.5 Sodium Nitrite², g6.3 Total Weight Aqueous Phase, g 2100.0 ¹Dispersant may be any of thoselisted in Dispersant Table 5. ²Values are for anhydrous salts.

The dispersants that can be used in the manufacturing of the polymersand that provide hemocompatibility to the polymeric bead surface are setforth in Table 5 below. In one embodiment, the dispersants provide thehemocompatible and/or biocompatible properties of the polymeric beadsurfaces.

TABLE 5 Dispersant List Poly(N-vinylpyrrolidinone); BASF Luviskol K60Sodium Polyacrylate Poly(hydroxyethyl acrylate) Poly(hydroxypropylacrylate) Poly(hydroxyethyl methacrylate) Poly(hydroxypropylmethacrylate) Carrageenan; FMC Kappa and Lambda Guar Gum Derivatives:Stein-Hall Jaguar HP-11; Hydroxypropyl Guar Gum Jaguar CMHP; Sodium Saltof Carboxymethyl, hydroxypropyl Guar Gum

The organic phase composition for the aromatic, crosslinked gel polymerof the present invention is set forth in Table 6 below:

TABLE 6 Organic Phase Composition For an Aromatic, Crosslinked GelPolymer Styrene, wt. % 91.0 Divinylbenzene (DVB), wt. % 5.0Ethylvinylbenzene EVB, wt. % 4.0 Total Polymerizable Monomers, wt. %100.0 Benzoyl Peroxide (Pure), wt. % of 0.5 Polymerizable Monomers

The organic phase charges for an aromatic, crosslinked gel polymerprepared in a five (5) liter reactor is set forth in Table 7 below:

TABLE 7 Organic Phase Charges For an Aromatic, Crosslinked Gel PolymerPrepared in a Five (5) Liter Reactor Styrene, g 1565.2 Divinylbenzene(DVB), g Pure (86.0) From Commercial 55% DVB of Composition 55 wt. %DVB, 44 wt. % EVB, and 1 wt. % Inerts Ethylvinylbenzene (EVB), g (68.8)Commercial 55% DVB, g 156.364 Inerts, g (1.564) Weights in Parenthesisare Part of Commercial DVB Total Weight of Organic Phase Excluding BPO,g 1721.564 Benzoyl Peroxide, 75 wt. % active, g 11.467

The dispersion mixture for a five (5) liter reactor for preparingaliphatic polymers of the present invention is set forth in Table 8below:

TABLE 8 Dispersion Mixture For Five (5) Liter Reactor For PreparingAliphatic Polymers Aq/Org. Vol. Ratio 1.1 Volume of Organic Phase 1900.0ml Volume of Aqueous Phase 2090.0 ml Density of organic Phase 0.963194g/ml Weight of Organic Phase 1830.07 g Density of Aqueous Phase 1.005g/ml Weight of Aqueous Phase 2153.95 g Polymerizable Monomers; 1830.07 gMethyl Acrylate (MA) and Trimethylolpropane Trimethacrylate (TMPTMA)Total Volume of Organic & Aqueous Phases 3990.0 ml Total Weight ofOrganic & Aqueous Phases 3930.52 g

The aqueous phase composition for preparing the aliphatic, crosslinkedgel polymers of the present invention is set forth in Table 9 below:

TABLE 9 Aqueous Phase Composition For Preparing Aliphatic, CrosslinkedPolymers Ultrapure Water, wt. % 95.7 Dispersant¹ (Pure), wt. % 0.500Sodium Carbonate², wt. % 0.500 Sodium Nitrite², wt. % 0.300 SodiumSulfate², wt. % 3.0 ¹Dispersant may be anyone of those listed inDispersant Table (Table 5). ²All the salts are computed on an anhydroussalt basis.

The aqueous phase charges for preparing aliphatic, crosslinked gelpolymers of in a five (5) liter reactor is set forth in Table 10 below:

TABLE 10 Aqueous Phase Charges For Preparing Aliphatic, CrosslinkedPolymers in a Five (5) Liter Reactor Ultrapure Water 2061.33 Dispersant¹(Pure), g 10.77 Sodium Carbonate², g 10.77 Sodium Nitrite², g 6.46Sodium Sulfate², g 64.62 Total Weight Aqueous Phase, g 2153.95¹Dispersant may be anyone of those listed in Dispersant Table (Table 5).²All the salts are computed on an anhydrous salt basis.

The organic phase composition for an aliphatic, crosslinked gel polymerof the present invention is set forth in Table 11 below:

TABLE 11 Organic Phase Composition For An Aliphatic, Crosslinked GelPolymer Methyl Acrylate (MA), wt. % 90.0 TrimethylolpropaneTrimethacrylate (TMPTMA) wt. % 10.0 Total Polymerizable Monomers, wt. %100.0 Benzoyl Peroxide (Pure), wt. % of 0.5 Polymerizable Monomers

The organic phase charges for an aliphatic, crosslinked gel polymer ofone of the embodiments of the polymers of the present invention is setforth in Table 12 below:

TABLE 12 Organic Phase Charges For An Aliphatic, Crosslinked Gel PolymerPrepared in a Five (5) Liter Reactor Methyl Acrylate (MA) 1647.1 gTrimethylolpropane Trimethacrylate (TMPTMA) 183.0 g Total Weight ofOrganic Phase Excluding 1830.1 g Benzoyl Peroxide (BPO) BenzoylPeroxide, 75 wt. % active, g 12.2 g

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the attendant claims attachedhereto, this invention may be practiced otherwise than as specificallydisclosed herein.

1. A crosslinked polymer for binding phosphate anions, said polymercomprising at least one polyvalent cation bound to said polymer andwherein said cation functions as the binding site for phosphate anionsto thereby capture said phosphate anions.
 2. The polymer of claim 1wherein said polymer is selected from a group consisting ofdivinylbenzene, styrene, ethylvinylbenzene, acrylic acid, methacrylicacid, esters of acrylic acid, esters of methacrylic acid, maleic acidand esters thereof, itaconic acid and esters thereof, trimethylolpropanetrimethacrylate, trimethylolpropane triacrylate, and mixtures thereof.3. The polymer of claim 1 wherein said cation is attached to saidpolymer through at least one anionic group, said anionic group isselected from a group consisting of sulfonate, carboxylate, phosphonateand mixtures thereof.
 4. The polymer of claim 1 wherein said cation isselected from a group consisting of aluminum, calcium, magnesium,molybdenum, manganese, titanium, barium, strontium, zirconium, vanadium,scandium, lanthanum, yttrium, cerium, nickel, iron, copper, cobalt,chromium, zinc and mixtures thereof.
 5. The polymer of claim 1 whereinsaid polymer is a hemocompatible polymer.
 6. The polymer of claim 1wherein said polymer is selected from a group consisting ofbiocompatible polymers, biocompatible porous polymers, biocompatiblenon-porous polymers and mixtures thereof.
 7. The polymer of claim 1wherein said polymer binds to phosphate anions in a human bodily fluidenvironment.
 8. The polymer of claim 7 wherein the human bodily fluidenvironment is selected from a group consisting of whole blood, lymphfluid, blood plasma and mixtures thereof.
 9. A crosslinked polymer forbinding phosphate anions, said polymer comprising a polyvalent cationattached to said polymer through at least one covalently bound anionicfunctional group wherein said cation functions as the binding site forphosphate anions to thereby capture said phosphate anions.
 10. Thepolymer of claim 9 wherein said polymer is selected from a groupconsisting of divinylbenzene, styrene, ethylvinylbenzene, acrylic acid,methacrylic acid, esters of acrylic acid, esters of methacrylic acid,maleic acid and esters thereof, itaconic acid and esters thereof,trimethylolpropane trimethacrylate, trimethylolpropane triacrylate, andmixtures thereof.
 11. The polymer of claim 9 wherein said anionicfunctional group is selected from a group consisting of sulfonate,carboxylate, phosphonate and mixtures thereof.
 12. The polymer of claim9 wherein said cation is selected from a group consisting of aluminum,calcium, magnesium, molybdenum, manganese, titanium, barium, strontium,zirconium, vanadium, scandium, lanthanum, yttrium, cerium, nickel, iron,copper, cobalt, chromium, zinc and mixtures thereof.
 13. A polymer forremoving phosphate anions from a human bodily fluid environment, saidpolymer is manufactured by a method comprising: forming a crosslinkedpolymer, covalently attaching at least one anionic group to saidpolymer, and binding at least one polyvalent cation onto said anionicgroup attached to said polymer wherein said cation functions as thebinding site for phosphate anions to thereby capture said phosphateanions.
 14. The polymer of claim 13 wherein said polymer is selectedfrom a group consisting of divinylbenzene, styrene, ethylvinylbenzene,acrylic acid, methacrylic acid, esters of acrylic acid, esters ofmethacrylic acid, maleic acid and esters thereof, itaconic acid andesters thereof, trimethylolpropane trimethacrylate, trimethylolpropanetriacrylate, and mixtures thereof.
 15. The polymer of claim 13 whereinsaid anionic group is selected from a group consisting of sulfonate,carboxylate, phosphonate and mixtures thereof.
 16. The polymer of claim13 wherein said cation is selected from a group consisting of aluminum,calcium, magnesium, molybdenum, manganese, titanium, barium, strontium,zirconium, vanadium, scandium, lanthanum, yttrium, cerium, nickel, iron,copper, cobalt, chromium, zinc and mixtures thereof.
 17. The polymer ofclaim 13 wherein said polymer is a hemocompatible polymer and the humanbodily fluid environment is selected from a group consisting of wholeblood, lymph fluid, blood plasma and mixtures thereof.
 18. A method ofmanufacturing a polymer for binding phosphate anions, said methodcomprising: forming a crosslinked polymer, covalently attaching at leastone anionic group to said polymer, and binding at least one polyvalentcation onto said anionic group attached to said polymer to form a ligandwhereby said ligand is design to remove phosphate anions to therebycapture said phosphate anions.
 19. The method of claim 18 whereinwherein said polymer is selected from a group consisting ofdivinylbenzene, styrene, ethylvinylbenzene, acrylic acid, methacrylicacid, esters of acrylic acid, esters of methacrylic acid, maleic acidand esters thereof, itaconic acid and esters thereof, trimethylolpropanetrimethacrylate, trimethylolpropane triacrylate, and mixtures thereof.20. The method of claim 16 wherein said anion is selected from a groupconsisting of sulfate, carboxylate, phosphate and mixtures thereof andsaid cation is selected from a group consisting of aluminum, calcium,magnesium, molybdenum, manganese, titanium, barium, strontium,zirconium, vanadium, scandium, lanthanum, yttrium, cerium, nickel, iron,copper, cobalt, chromium, zinc and mixtures thereof.